30678 Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules DEPARTMENT OF HEALTH AND agency's investigations and analyses of the United States (Refs. 1 through 3). HUMAN SERVICES these illnesses and injuries. FDA is also The ingredient sources of the ephedrine incorporating by reference its alkaloids include raw botanicals and Food and Drug Administration Laboratory Information Bulletin (LIB) extracts from botanical sources. Ma No. 4053, that FDA will use in huang, Ephedra, Chinese Ephedra, and 21 CFR Part 111 determining the level of ephedrine epitonin are several names used for [Docket No. 95N±0304] alkaloids in a dietary supplement. botanical products, primarily from DATES: Written comments by August 18, Ephedra sinica Stapf, E. equistestina RIN 0901±AA59 1997. The agency proposes that any Bunge, E. intermedia var. tibetica Stapf Dietary Supplements Containing final rule that may issue based on this and E. distachya L. (the Ephedras), that Ephedrine Alkaloids proposal become effective 180 days after are sources of ephedrine alkaloids. date of publication of the final rule. These alkaloids, ephedrine, AGENCY: Food and Drug Administration, ADDRESSES: Submit written requests for pseudoephedrine, norpseudoephedrine, HHS. single copies of the analytical method norephedrine, methylephedrine, ACTION: Proposed rule. LIB No. 4053 to the Director, Office of methylpseudoephedrine, and related Constituent Operations, Industry alkaloids, are naturally occurring SUMMARY: The Food and Drug Activities Staff (HFS±565), Food and chemical stimulants (Refs. 4 through 8). Administration (FDA) is proposing to Drug Administration, 200 C St. SW., rm. Although the proportions of the various make a finding, which will have the 5827, Washington, DC 20204. Send two ephedrine alkaloids in botanical species force and effect of law, that a dietary self-addressed adhesive labels to assist vary from one species to another, in supplement is adulterated if it contains that office in processing your requests. most species used commercially, 8 milligrams (mg) or more of ephedrine Submit written comments to the ephedrine is the most predominant alkaloids per serving, or if its labeling Dockets Management Branch (HFA± alkaloid. suggests or recommends conditions of 305), Food and Drug Administration, The ephedrine and related alkaloids use that would result in intake of 8 mg 12410 Parklawn Dr., rm. 1±23, are amphetamine-like compounds. They or more in a 6-hour period or a total Rockville, MD 20857. Requests and exhibit some common types of effects daily intake of 24 mg or more of comments should be identified with the but vary in the relative intensity of these ephedrine alkaloids; require that the docket number found in brackets in the effects (Table 1) (Refs. 5, 6, and 9 label of dietary supplements that heading of this document. A copy of the through 15). For example, ephedrine is contain ephedrine alkaloids state ``Do analytical method LIB No. 4053, a cardiovascular system (CVS) and not use this product for more than 7 redacted adverse event reports (AER's) days''; prohibit the use of ephedrine associated with the use of dietary nervous system (NS) stimulant. alkaloids with ingredients, or with supplements containing ephedrine Pseudoephedrine has some CVS and NS ingredients that contain substances, that alkaloids as well as copies of any stimulatory effects but is less potent have a known stimulant effect (e.g., accompanying medical records, and than ephedrine. Norephedrine (also sources of caffeine or yohimbine), received comments are available for called phenylpropanolamine) is similar which may interact with ephedrine public examination in the Dockets to ephedrine in its NS stimulant effects alkaloids; prohibit labeling claims that Management Branch between 9 a.m. and but has fewer CVS stimulant effects than require long-term intake to achieve the 4 p.m., Monday through Friday. ephedrine (Refs. 12 and 16 through 18). Although norephedrine is often a minor purported effect (e.g., weight loss and FOR FURTHER INFORMATION CONTACT: ephedrine alkaloid constituent, in body building); require a statement in Margaret C. Binzer, Center for Food humans it can be produced from conjunction with claims that encourage Safety and Applied Nutrition (HFS± ingested ephedrine through normal short-term excessive intake to enhance 456), Food and Drug Administration, the purported effect (e.g., energy) that 200 C St. SW., Washington, DC 20204, metabolic processes (Refs. 9, 19, and ``Taking more than the recommended 202±401±9859, FAX 202±260±8957, or 20). Thus, its presence in body tissues serving may result in heart attack, E-mail [email protected]. and fluids may be detected, and its stroke, seizure or death''; and require physiological effects can occur, even if specific warning statements to appear SUPPLEMENTARY INFORMATION: norephedrine is not contained in on product labels. FDA is proposing I. Background meaningful amounts in the original these actions in response to serious supplement product. Data on the other illnesses and injuries, including A. Characteristics of Ephedrine ephedrine alkaloids and related multiple deaths, associated with the use Alkaloids alkaloids are limited, and thus their of dietary supplement products that Dietary supplements containing physiological and pharmacological contain ephedrine alkaloids and the ephedrine alkaloids are widely sold in effects are largely unknown (Ref. 15). TABLE 1.ÐPATTERNS OF SIGNS AND SYMPTOMS ASSOCIATED WITH DIETARY SUPPLEMENTS CONTAINING EPHEDRINE ALKALOIDS Organ/system involved Clinical significance Signs and symptoms Cardiovascular system ......... Serious ............................... Dysrhythmias, severe hypertension, cardiac arrest, angina, myocardial infarction, and stroke 1 Less clinically significant .... Tachycardia, mild hypertension, palpitations. Nervous system ................... Serious ............................... Psychosis, suicidal, altered or loss of consciousness (including disorientation or confusion), and seizures. Less clinically significant .... Anxiety, nervousness, tremor, hyperactivity, insomnia, altered behavior, memory changes. Gastrointestinal (GI) ............. Serious ............................... Altered serum enzymes, hepatitis. Less clinically significant .... GI distress (nausea, vomiting, diarrhea, constipation). Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / Proposed Rules 30679 TABLE 1.ÐPATTERNS OF SIGNS AND SYMPTOMS ASSOCIATED WITH DIETARY SUPPLEMENTS CONTAINING EPHEDRINE ALKALOIDSÐContinued Organ/system involved Clinical significance Signs and symptoms Dermatologic ........................ Serious ............................... Exfoliative dermatitis. Less clinically significant .... Nonspecific rashes. General manifestations ........ ............................................ Numbness, tingling, dizziness, fatigue, lethargy, weakness. 1 For the purposes of this document, strokes (i.e., cerebrovascular accidents) are considered to be related to the cardiovascular system, be- cause predisposing or inciting factors include hypertension, dysrhythmias and ischemia, although it is recognized that the consequences affect the central nervous system. B. The Availability of Ephedrine 25). Results of the analyses show that The AER's associated with the Alkaloids these products, taking into account the ephedrine alkaloid-containing products To determine the types of ephedrine labeled recommended serving included consistent patterns of signs alkaloid-containing dietary supplements instructions, are likely to provide and symptoms among both otherwise available in the marketplace, the agency intakes of ephedrine alkaloids that range healthy individuals and those with has collected over 125 dietary from below the detectible limits of underlying diseases or conditions. supplement products labeled as FDA's analytical method to 110 mg per These signs and symptoms included containing a known source of ephedrine serving (i.e., per single use) (Refs. 1, 2, rapid and irregular heart rhythms, alkaloids during the past 2 years (Refs. 21, 25, and 26). Most of the products, increased blood pressure, chest pain, 1 and 2). These products show that regardless of their promoted use, had anxiety, nervousness, tremor, ephedrine alkaloid-containing-dietary ephedrine alkaloid levels at or above 10 hyperactivity, and insomnia (i.e., supplements are marketed in a variety mg per serving. inability or difficulty in sleeping) and of forms, including capsules, tablets, Many of the dietary supplement were associated with clinically powders, and liquids. The source of the products that FDA collected were significant conditions, including heart ephedrine alkaloids in these promoted for uses such as weight loss, attack, stroke, psychoses, seizure, and, supplements vary from the raw body building, increased energy, in a few cases, death. Many of these botanical to powdered plant material increased mental concentration, signs and symptoms occurred in young and concentrated extracts; however, increased sexual sensations, or euphoria adults who generally would not have most of the products contain or as alternatives to illicit street drugs been expected to be at high risk for such concentrated extracts. Although FDA is (Refs. 1, 2, and 25). The majority of the conditions (e.g., heart attack and stroke). aware that some companies have products collected also bore warning Many adverse events were reported to changed their labeling and formulation statements on their